Cancer Cell cycle, oncogenes and tumour suppressors

Jake Turner

Your (relevant) learning objectives• List the phases of the cell cycle and define the functions of each component• Explain the control mechanisms utilised during the cell cycle• Recognise the role of malfunctioning of these control mechanisms in

neoplasia• Explain the function of oncogenes and tumour suppressor genes in the

normal cell and the changes which occure in neoplasia.• Describe the role of the following oncogenes: ras, c-myc and c-erbB-2 and

their significance in treatment.• Describe the role of the following tumour suppressor genes: retinoblastoma

and p53• Outline the features of inherited susceptibility to the development of

neoplasms, using Xeroderma Pigmentosum and Ataxia Telangectasia as examples.

• Describe the alterations to DNA which cause neoplasia

Learning objectives (slightly) simplified

• Understand the cell cycle checkpoints, what they check and what genes are in control

• Know the phases of the cell cycle and what happens in each• Understand oncogenes and tumour suppressor genes

(normal and cancer)• Describe the role of the oncogenes ras, c-myc and c-erbB-2

and their significance in treatment.• Describe the role of the tumour suppressor genes

retinoblastoma and p53• Understand inherited susceptability to cancer (e.g. XP and

Ataxia telangiectasia)

Background

• How many mutational insults do we take each day?– We have ~10^12 cells in our body– Each receives ~ 10,000 mutational insults each day

(mainly from free oxygen radicals and background radiation)

– This gives us 10^16 mutations per day!

REMINDER: Tumours develop from a single cell – they form a monoclonal population arising from a single cell.

Why don’t we all have cancer?

• 10,000 mutations per cell = 0.000165% of our DNA

• Gene deserts • Non functional mutations• DNA repair processes (99.9999% effective)• Non oncogene mutations • Tumour suppressors (senescence or apoptosis)• Immune destruction of abnormal cells• Knudson’s two hit hypothesis

Types of mutations

• Single Nucleotide Polymorphism• Double strand breaks• Mismatch• Frame-shift• Nonsense• Missense• Deletion• Insertion• Translocation & other chromosomal aberrations• Repeat expansion

Types of DNA repair

• Direct repair• Excision repair (can

be base or nucleotide excision)

• Mismatch repair• Recombination repair

The cell cycle

• G0 Resting• G1 (Gap 1 – normal cell

function)• S Phase DNA replicates• G2 (Gap 2 – growth in

preparation for M phase)• M Phase Nuclear & cytoplasmic

division– M phase consists of prophase, metaphase,

anaphase, telophase and cytokinesis in the classical cell cycle.

What controls the checkpoints?

• Cyclin dependant kinases• G1/S phase checkpoint is

controlled by P53 and Rb.– Rb– Unphosphorylated state binds E2F

transcription factor. Phosphorylated state releases E2F and allows passage into S phase.

– P53– Senses DNA damage– Induces p21 (CKI) stops progression

Oncogenes

• What are oncogenes?– Genes that, when activated by e.g. mutations,

predispose people to getting cancer.– They can be very specific, e.g. Retinoblastoma

gene, Or very non specific, e.g. ras mutations.• Some examples of oncogenes are

– ras – c-myc– c-erbB-2

Oncogenes• Ras

– Mutation is most common abnormality of dominant oncogenes – 15-20% of tumours

– Normally inactivated by hydrolysis of GTP, blocked when mutated

• c-myc– Transcriptional activator– Targets include cyclin D2– Translocation t(8,14) in Burkitt lymphoma, but also breast, colon & lung cancer

• HER2 (c-erbB-2)– Human Epithelial growth Receptor (cell surface receptor)– Amplified in 25-30% of breast cancers– Herceptin is a specifically targeted therapy for HER2 positive breast cancer

How are proto-oncogenes activated into oncogenes?

E.g. Ras

E.g. Myc, HER2

E.g. BCR-Abl translocation

Tumour suppressor genes

• What are tumour suppressor genes?– Genes that, when Inactivated by e.g. mutations,

predispose people to cancer• Examples of tumour suppressor genes

– Retinoblastoma– p53

Tumour suppressor genes• p53

– Acts at G1/S checkpoint– Surveillance in cell cycle, normally stops cell cycle progression of damaged cells or causes

apoptosis in non-repairable DNA damage– Induces transcription of genes which repair DNA– Mutated in a large number of cancers (>50%) and associated with invasion

– HPV (human papilloma virus) and cervical carcinoma • E6 and E7 antigens inactivate p53• HPV 16 and 18 most active serotypes

• Retinoblastoma– Autosomal dominant (40%) OR sporadic (60%)– Inherited on defective copy of RB gene– 2nd hit = spontaneous mutation > retinoblastoma (& osteosarcomas)– Remember RB protein normally binds E2F– When E2F released cell can enter cycle (at G1 phase)

P53

Mechanism of action of Rb

Douglas Hanahan , Robert A. Weinberg, Hallmarks of Cancer: The Next Generation (2011)

Do not learn these!HER2

What if…

• What happens if we have a mutation that causes our tumour suppressors to go into overdrive?

Progeria and Progeroid syndromes• Excessive apoptosis of abnormal cells leads to

the appearance of rapid aging• Can be caused by a single base pair mutation

in the LMNA gene.

Hutchinson-Gilford progeria syndrome

Werner syndrome

Xeroderma pigmentosum• Autosomal Recessive

Deficiency of DNA repair enzymes

• Young children develop skin atrophy & cancers, normally seen in elderly people

• Death often due to metastatic squamous cell carcinoma or melanoma

• Fewer than 40% survive beyond 20 years

Ataxia telangiectasia

• Autosomal Recessive• Deficiency of DNA repair

enzymes (ATM)• 1 in 40,000 to 100,000• Progressive cerebellar ataxia

beginning between ages one and four years

• Increased risk of leukaemia and lymphoma

• unusually sensitive to ionizing radiation

Douglas Hanahan , Robert A. Weinberg, Hallmarks of Cancer: The Next Generation (2011)

Douglas Hanahan , Robert A. Weinberg, Hallmarks of Cancer: The Next Generation (2011)

Learning objectives (slightly) simplified

• Understand the cell cycle checkpoints, what they check and what genes are in control

• Know the phases of the cell cycle and what happens in each• Understand oncogenes and tumour suppressor genes

(normal and cancer)• Describe the role of the oncogenes ras, c-myc and c-erbB-2

and their significance in treatment.• Describe the role of the tumour suppressor genes

retinoblastoma and p53• Understand inherited susceptibility to cancer (e.g. XP and

Ataxia telangiectasia)

Any questions?